Gamma-Secretase is a protease that catalyzes intramembrane cleavage of an expanding list of substrates. One of the[unreadable] actions of gamma-secretase is to cleave Abeta from its precursor (APP). As Abeta accumulation is thought to play a[unreadable] causal role in the development of Alzheimer's Disease (AD) and gamma-secretase inhibitors block Abeta production,[unreadable] gamma-secretase has come under intense scrutiny as a potential target for AD therapeutics. As a result, highly[unreadable] potent inhibitors of gamma-secretase with excellent in vivo pharmacologic properties have been developed as[unreadable] potential therapeutic agents for AD. It is believed that such inhibitors will lower Abeta in vivo, prevent its[unreadable] accumulation, and may have beneficial effect on AD. However, it is also believed that the utility of gamma-secretase[unreadable] inhibitors will be limited due to inhibition of gamma-secretase regulated signaling events mediated by[unreadable] other substrates, especially signaling events mediated by Notch. Our preliminary data indicates that these gamma- secretase inhibitors may have therapeutic utility in such diverse settings as AD, cancer, multiple sclerosis, and[unreadable] immune rejection. Thus, the overall thrust of this program project is to utilize an orally bioavailable gamma-secretase[unreadable] inhibitor to rigorously evaluate its therapeutic potential. More specifically, we hypothesize that in[unreadable] certain conditions inhibition of APP processing, Notch signaling, and other physiologic effects of a gamma-secretase[unreadable] inhibitor will have beneficial effects that outweigh potential toxicities. hi this project we will 1)[unreadable] develop biomarker assays that will enable us to evaluate the extent of Notch inhibition in vivo, 2) use gamma-secretase[unreadable] inhibitors to explore the relationship between extent of Abeta reduction in vivo and alteration in Abeta[unreadable] deposition 3) obtain information on dosing, degree of inhibition of APP and Notch, and toxicity vital to the[unreadable] other projects and 4) explore the role of Notch singling and the effect of gamma-secretase mediated inhibition of[unreadable] that signaling in a mouse model of toxin induced demyelination and experimental autoimmune encephalitis.